Determinants of adherence to recommendations on physical activity, red and processed meat intake, and body weight among lynch syndrome patients.

This study aimed to identify determinants of adherence to lifestyle and body weight recommendations for cancer prevention among Lynch Syndrome (LS) patients. Cross-sectional baseline data of LS patients participating in the Lifestyle & Lynch (LiLy) study was used to assess determinants of adherence to the World Cancer Research Fund cancer prevention recommendations on body weight, physical activity, and red and processed meat intake. Adherence and potential determinants of adherence were assessed using questionnaires. Multivariable logistic regression analyses were conducted to identify determinants of adherence. Of the 211 participants, 50.2% adhered to the body weight recommendation, 78.7% adhered to the physical activity recommendation, and 33.6% adhered to the red and processed meat recommendation. Being younger and having a higher level of education were associated with adherence to the recommendation on body weight. Having knowledge about the recommendation was associated with adherence to the recommendations on physical activity and red and processed meat. Results confirm that knowledge about recommendations for cancer prevention is an important determinant for adherence and suggest that strategies to increase knowledge should be included in lifestyle promotion targeted at LS patients, along with behavior change techniques influencing other modifiable determinants.

Recommendations on Surveillance for Differentiated Thyroid Carcinoma in Children with PTEN Hamartoma Tumor Syndrome.

BACKGROUND: PTEN hamartoma tumor syndrome (PHTS) represents a group of syndromes caused by a mutation in the PTEN gene. Children with a germline PTEN mutation have an increased risk of developing differentiated thyroid carcinoma (DTC). Several guidelines have focused on thyroid surveillance in these children, but studies substantiating these recommendations are lacking. OBJECTIVE: The present study intends to provide the available evidence for a thyroid carcinoma surveillance program in children with PHTS. METHODS: An extensive literature search was performed to identify all studies on DTC in pediatric PHTS patients. Two pediatric cases are presented to illustrate the pros and cons of thyroid carcinoma surveillance. Recommendations for other patient groups at risk for DTC were evaluated. Consensus within the study team on recommendations for children with PHTS was reached by balancing the incidence and behavior of DTC with the pros and cons of thyroid surveillance, and the different surveillance methods. RESULTS: In 5 cohort studies the incidence of DTC in childhood ranged from 4 to 12%. In total 57 cases of DTC and/or benign nodular disease in pediatric PHTS patients were identified, of which 27 had proven DTC, with a median age of 12 years (range 4-17). Follicular thyroid carcinoma (FTC) was diagnosed in 52% of the pediatric DTC patients. No evidence was found for a different clinical behavior of DTC in PHTS patients compared to sporadic DTC. CONCLUSIONS: Children with PHTS are at increased risk for developing DTC, with 4 years being the youngest age reported at presentation and FTC being overrepresented. DTC in pediatric PHTS patients does not seem to be more aggressive than sporadic DTC. RECOMMENDATIONS: Surveillance for DTC in pediatric PHTS patients seems justified, as early diagnosis may decrease morbidity. Consensus within the study team was reached to recommend surveillance from the age of 10 years onwards, since at that age the incidence of DTC seems to reach 5%. Surveillance for DTC should consist of yearly neck palpation and triennial thyroid ultrasound. Surveillance in children with PHTS should be performed in a center of excellence for pediatric thyroid disease or PHTS.

Romidepsin suppresses monosodium urate crystal-induced cytokine production through upregulation of suppressor of cytokine signaling 1 expression.

BACKGROUND: Acute gouty arthritis currently is the most common form of inflammatory arthritis in developed countries. Treatment is still suboptimal. Dosage of urate-lowering therapy is often too low to reach target urate levels, and adherence to therapy is poor. In this study, we therefore explore a new treatment option to limit inflammation in acute gout: specific histone deacetylase (HDAC) inhibition. METHODS: Peripheral blood mononuclear cells (PBMCs) were cultured with a combination of monosodium urate crystals (MSU) and palmitic acid (C16.0) in order to activate the NLRP3 inflammasome and induce IL-1ß production. HDAC inhibitors and other compounds were added beforehand with a 1-h pre-incubation period. RESULTS: The HDAC1/2 inhibitor romidepsin was most potent in lowering C16.0+MSU-induced IL-1ß production compared to other specific class I HDAC inhibitors. At 10 nM, romidepsin decreased IL-1ß, IL-1Ra, IL-6, and IL-8 production. IL-1ß mRNA was significantly decreased at 25 nM. Although romidepsin increased PTEN expression, PBMCs from patients with germline mutations in PTEN still responded well to romidepsin. Romidepsin also increased SOCS1 expression and blocked STAT1 and STAT3 activation. Furthermore, experiments with bortezomib showed that blocking the proteasome reverses the cytokine suppression by romidepsin. CONCLUSIONS: Our results show that romidepsin is a very potent inhibitor of C16.0+MSU-induced cytokines in vitro. Romidepsin upregulated transcription of SOCS1, which was shown to directly target inflammatory signaling molecules for proteasomal degradation. Inhibiting the proteasome therefore reversed the cytokine-suppressive effects of romidepsin. HDAC1/2 dual inhibition could therefore be a highly potent new treatment option for acute gout, although safety has to be determined in vivo.

An online self-test added to colorectal cancer screening can increase the effectiveness of familial cancer risk assessment without increasing distress.

AIM: Most people who are at increased familial colorectal cancer (FCRC) risk are not identified, despite the need for enhanced surveillance colonoscopy for effective CRC prevention. An online self-test may enhance this identification. We assessed whether taking an online self-test to identify increased FCRC risk increases anxiety, distress or CRC risk perception in population-based CRC screening. METHOD: After the precolonoscopy consultation, patients who had a positive immunohistochemical occult faecal blood test (iFOBT+) in population-based CRC screening were invited by email to take an online self-test at home which returned details of family history. Anxiety (STAI-DY), distress (HADS) and CRC risk perception were assessed immediately before and after taking the online self-test and 2 weeks later. RESULTS: Of 250 participants invited, 177 (71%) completed the online self-test and psychological questionnaires and 153 (61%) completed questionnaires 2 weeks later. The median age was 65 years (range 61-75). The FCRC risk was increased in 17 participants (9.6%). Of these, 12 (6.8%) had a highly increased FCRC risk and may benefit from germline genetic testing for Lynch syndrome. In 7 of 17 participants (40%) the self-test obtained novel information on family history. Anxiety and distress levels were, and remained, below a clinically relevant level. Perception of CRC risk remained unchanged. Most participants (83%) would recommend the online self-test to others. CONCLUSION: Of those with a iFOBT+, 9.6% had a previously unidentified increasedFCRC risk and require an enhanced surveillance colonoscopy instead of iFOBT. As screening for this risk did not increase anxiety or distress, and was highly acceptable, we recommend adding the online self-test to population-based CRC screening.

[Does ovarian cancer start in the fallopian tubes? Possible implications for preventive adnexal removal]. / Begint ovariumcarcinoom in de tubae?

BACKGROUND: Recent insights in high-grade serous ovarian cancer development are pointing to the fallopian tubes as likely place of origin and not the ovaries themselves. This may have consequences for patients with increased risk of ovarian cancer. Adnexal removal is currently recommended for this patient group at an age of 35-45, which leads to premature menopause. CASE DESCRIPTION: In a 55-year-old woman with a BRCA1 germ line mutation, a high-grade serous carcinoma was unexpectedly diagnosed in both fallopian tubes during preventive adnexal removal. Her ovaries did not have any abnormalities. CONCLUSION: This case illustrates a fallopian tube origin for high-grade serous ovarian cancer development in a carrier of a BRCA1 germ line mutation. In the future, salpingectomy could play a role in ovarian cancer prevention. However, research is needed first to demonstrate the safety of this strategy. Salpingectomy in women with a BRCA germ line mutation should therefore only be performed in the context of research for the time being.

[European Reference Networks for rare diseases]. / Europese referentienetwerken voor zeldzame ziekten.

Approximately one million patients in the Netherlands and 27-36 million patients in Europe have one of the 5,000-8,000 known rare diseases. These patients often do not receive the care they need or with a substantial delay from diagnosis to treatment. As of March 2017, 24 European Reference Networks (ERNs) were launched with the aim to improve the care for these patients through cross-border healthcare, where in principle the knowledge travels and not the patient. It is expected that through the ERNs, European patients with a rare disease get more often and more quickly access to expert care and that it will accelerate guideline development and research. In each of the 24 ERNs, one or more Dutch expertise centres for rare diseases participate, and 5 ERNs are coordinated by centres from the Netherlands.

Increasing awareness and knowledge of lifestyle recommendations for cancer prevention in Lynch syndrome carriers: Randomized controlled trial.

Lynch syndrome (LS) mutation carriers may reduce their cancer risk by adhering to lifestyle recommendations for cancer prevention. This study tested the effect of providing LS mutation carriers with World Cancer Research Fund-the Netherlands (WCRF-NL) health promotion materials on awareness and knowledge of and adherence to these recommendations. In this randomized controlled trial (n = 226), the intervention group (n = 114) received WCRF-NL health promotion materials. All LS mutation carriers were asked to fill out questionnaires at 2 weeks before (baseline, T0) and at 2 weeks (T1) and 6 months (T2) after the intervention. Linear mixed models were performed on awareness (0-7) and knowledge (0-7) of the recommendations, and on the secondary outcomes, that is adherence, distress, cancer worry, and risk perception. Compared with the control group, the intervention group became significantly more aware (overall mean difference = 1.24; 95%CI = 0.82-1.67) and obtained significantly improved knowledge of the recommendations (overall mean difference = 1.65; 95%CI = 1.27-2.03). Differences were significantly larger for T1 (Pinteraction = .003 and ≤.001, respectively) but remained significant for T2. No effect on secondary outcomes was found. In conclusion, provision of WCRF-NL health promotion materials increases awareness and knowledge of lifestyle recommendations for cancer prevention among LS mutation carriers without causing additional distress, but does not affect adherence.

Online self-test identifies women at high familial breast cancer risk in population-based breast cancer screening without inducing anxiety or distress.

INTRODUCTION: Identifying high familial breast cancer (FBC) risk improves detection of yet unknown BRCA1/2-mutation carriers, for whom BC risk is both highly likely and potentially preventable. We assessed whether a new online self-test could identify women at high FBC risk in population-based BC screening without inducing anxiety or distress. METHODS: After their visit for screening mammography, women were invited by email to take an online self-test for identifying highly increased FBC risk-based on Dutch guidelines. Exclusion criteria were previously diagnosed as increased FBC risk or a personal history of BC. Anxiety (State-Trait Anxiety Inventory Dutch Version), distress (Hospital Anxiety Depression Scale) and BC risk perception were assessed using questionnaires, which were completed immediately before and after taking the online self-test and 2 weeks later. RESULTS: Of the 562 women invited by email, 406 (72%) completed the online self-test while 304 also completed questionnaires (response rate 54%). After exclusion criteria, 287 (51%) were included for data analysis. Median age was 56 years (range 50-74). A high or moderate FBC risk was identified in 12 (4%) and three (1%) women, respectively. After completion of the online self-test, anxiety and BC risk perception were decreased while distress scores remained unchanged. Levels were below clinical relevance. Most women (85%) would recommend the self-test; few (3%) would not. CONCLUSION: The online self-test identified previously unknown women at high FBC risk (4%), who may carry a BRCA1/2-mutation, without inducing anxiety or distress. We therefore recommend offering this self-test to women who attend population-based screening mammography for the first time.

Childhood neuroendocrine tumours: a descriptive study revealing clues for genetic predisposition.

BACKGROUND: Neuroendocrine tumours (NETs) are rare in children and limited data are available. We aimed to specify tumour and patient characteristics and to investigate the role of genetic predisposition in the aetiology of paediatric NETs. METHODS: Using the Dutch Pathology Registry PALGA, we collected patient- and tumour data of paediatric NETs in the Netherlands between 1991 and 2013 (N=483). RESULTS: The incidence of paediatric NETs in the Netherlands is 5.40 per one million per year. The majority of NETs were appendiceal tumours (N=441;91.3%). Additional surgery in appendiceal NETs was indicated in 89 patients, but performed in only 27 of these patients. Four out of five patients with pancreatic NETs were diagnosed with Von Hippel-Lindau disease (N=2) and Multiple Endocrine Neoplasia type 1 (N=2). In one patient with an appendiceal NET Familial Adenomatous Polyposis was diagnosed. On the basis of second primary tumours or other additional diagnoses, involvement of genetic predisposition was suggestive in several others. CONCLUSIONS: We identified a significant number of patients with a confirmed or suspected tumour predisposition syndrome and show that paediatric pancreatic NETs in particular are associated with genetic syndromes. In addition, we conclude that treatment guidelines for appendiceal paediatric NETs need revision and improved implementation.

Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences.

The contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2, a member of the JAK tyrosine kinase family. These mutations were located in two adjacent codons of the pseudokinase domain (p.Pro760Leu and p.Gly761Val). In silico modeling revealed that both mutations affect the conformation of this autoregulatory domain. Consistent with this notion, both germline mutations promote TYK2 autophosphorylation and activate downstream STAT family members, which could be blocked with the JAK kinase inhibitor I. These data indicate that germline activating TYK2 mutations predispose to the development of ALL.

Lifestyle Risk Factors for Breast Cancer in BRCA1/2-Mutation Carriers Around Childbearing Age.

BRCA1/2-mutation carriers are at high risk of breast cancer (BC) and ovarian cancer. Physical inactivity, overweight (body mass index ≥25, BMI), smoking, and alcohol consumption are jointly responsible for about 1 in 4 postmenopausal BC cases in the general population. Limited evidence suggests physical activity also increases BC risk in BRCA1/2-mutation carriers. Women who have children often reduce physical activity and have weight gain, which increases BC risk. We assessed aforementioned lifestyle factors in a cohort of 268 BRCA1/2-mutation carriers around childbearing age (born between 1968 and 1983, median age 33 years, range 21-44). Furthermore, we evaluated the effect of having children on physical inactivity and overweight. Carriers were asked about lifestyle 4-6 weeks after genetic diagnosis at the Familial Cancer Clinic Nijmegen. Physical inactivity was defined as sports activity fewer than once a week. Carriers were categorized according to the age of their youngest child (no children, age 0-3 years and ≥4 years). In total, 48% of carriers were physically inactive, 41% were overweight, 27% smoked, and 70% consumed alcohol (3% ≥8 beverages/week). Physical inactivity was 4-5 times more likely in carriers with children. Overweight was not associated with having children. Carriers with children are a subgroup that may specifically benefit from lifestyle support to reduce BC risk.

Prospective Dutch colorectal cancer cohort: an infrastructure for long-term observational, prognostic, predictive and (randomized) intervention research.

BACKGROUND: Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG). METHODS/DESIGN: The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I-IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria. RESULTS: Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohort- or cmRCT-designed studies are currently recruiting patients. CONCLUSION: This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types.

Very high uptake of risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers: A single-center experience.

OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) is the only effective surgical strategy to reduce the increased risk of epithelial ovarian cancer in BRCA1/2 mutation carriers. Given the long-term health consequences of premature surgical menopause, we need insight in uptake and timing of RRSO to guide us in improving healthcare. METHODS: A single-center retrospective cohort study of BRCA1/2 mutation carriers diagnosed and counseled at the multidisciplinary Family Cancer Clinic of the Radboud university medical center in Nijmegen, The Netherlands, between 1999 and 2014. Descriptive statistics were used to analyze uptake and timing of RRSO. RESULTS: Data of 580 BRCA1/2 were analyzed. The uptake of RRSO among mutation carriers who are currently above the upper limit of the recommended age for RRSO, is 98.5% and 97.5% for BRCA1 and BRCA2 mutation carriers, respectively. The vast majority undergoes RRSO ≤40 (BRCA1) or ≤45 (BRCA2) years of age, provided that mutation status is known by that age: 90.8% and 97.3% of BRCA1 and BRCA2 mutation carriers, respectively. CONCLUSIONS: The uptake of RRSO among BRCA1/2 mutation carriers who were counseled at our Family Cancer Clinic is extremely high. High uptake might be largely attributed to the directive and uniform way of counseling by professionals at our Family Cancer Clinic. Given the fact that RRSO is often undergone at premenopausal age in our population, future research should focus on minimizing long-term health consequences of premature surgical menopause either by optimization of hormone replacement therapy or by investigating alternative strategies to RRSO.

Cardiovascular risk of BRCA1/2 mutation carriers: A review.

BRCA1/2 mutation carriers are at high risk of breast and ovarian cancer. The number of studies on non-cancer endpoints in BRCA1/2 mutation carriers is still limited. BRCA1/2 mutation carriers may be at higher cardiovascular risk due to early menopause after risk-reducing salpingo-oophorectomy and/or due to the potential cardiotoxic effects of breast cancer treatment (radiotherapy and chemotherapy). Moreover, BRCA genes have a role as a gatekeeper in cardiac function and structure, which may affect susceptibility to cardiac damage. Our goal is to review current knowledge of cardiovascular risk among BRCA1/2 mutation carriers.

The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery.

BACKGROUND: Colorectal cancer (CRC) is a cumulative term applied to a clinically and genetically heterogeneous group of neoplasms that occur in the bowel. Based on twin studies, up to 45 % of the CRC cases may involve a heritable component. Yet, only in 5-10 % of these cases high-penetrant germline mutations are found (e.g. mutations in APC and DNA mismatch repair genes) that result in a familial aggregation and/or an early onset of the disease. Genome-wide association studies have revealed that another ~5 % of the CRC cases may be explained by a cumulative effect of low-penetrant risk factors. Recent attempts to identify novel genetic factors using whole exome and whole genome sequencing has proven to be difficult since the remaining, yet to be discovered, high penetrant CRC predisposing genes appear to be rare. In addition, most of the moderately penetrant candidate genes identified so far have not been confirmed in independent cohorts. Based on literature examples, we here discuss how careful patient and cohort selection, candidate gene and variant selection, and corroborative evidence may be employed to facilitate the discovery of novel CRC predisposing genes. CONCLUSIONS: The picture emerges that the genetic predisposition to CRC is heterogeneous, involving complex interplays between common and rare (inter)genic variants with different penetrances. It is anticipated, however, that the use of large clinically well-defined patient and control datasets, together with improved functional and technical possibilities, will yield enough power to unravel this complex interplay and to generate accurate individualized estimates for the risk to develop CRC.

Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline.

Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence-based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2-2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9-2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1-4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacking. Based on these results, we propose that all female carriers of 40-50 years of age and female ATM c.7271T>G mutation carriers from 25 years of age onwards be offered intensified surveillance programs for breast cancer. Furthermore, all carriers should be made aware of lifestyle factors that contribute to the development of cardiovascular diseases and diabetes.

Improving recognition and referral of patients with an increased familial risk of colorectal cancer: results from a randomized controlled trial.

AIM: Only 12-49% of colorectal cancer (CRC) patients and their first-degree relatives with an increased familial CRC risk are referred for cancer prevention measures (surveillance colonoscopies or genetic counselling). The study was performed to evaluate the effectiveness and feasibility of a novel strategy to improve the uptake of genetic counselling for high risk individuals and surveillance colonoscopy for moderate risk groups. METHOD: Eighteen hospitals participated in a clustered randomized controlled trial. Patients in nine hospitals received usual care (group A). Nine other hospitals received the novel strategy (group B) including access to a website for patients and clinicians, patient-targeted brochures and clinician-targeted education and pocket referral cards. Data before and after dissemination of the strategy were collected from questionnaires and medical records. RESULTS: Data were complete for 358 (44%) of 820 CRC patients and 50 (36%) of 137 clinicians before dissemination of the strategy and 392/862 patients (45%) and 47/137 clinicians (34%) after. Referral for cancer prevention measures was assessed at a median of 8 (2-12) months after CRC diagnosis in groups A and B before the dissemination of the strategy and in group A after. In group B referral was assessed at a median of 9 (4-11) months after the dissemination of the strategy. Uptake of genetic counselling by high risk patients was equal in groups A and B, being 33% before and 15% after (P = 0.003). Uptake of surveillance colonoscopy by moderate risk relatives did not change significantly (group A, 36% before vs 41% after; group B, 33% before vs 19% after). In group B 94/140 patients (67%) and 25/72 clinicians (35%) visited the website and 34/140 (24%) patients read the brochure. Patients valued clinicians' information as most useful, followed by the patient brochure. Clinicians preferred pocket cards and education. CONCLUSION: Our strategy did not improve referral for cancer prevention measures. Although the newly offered strategy elements were appreciated, patients preferred clinicians' advice regarding referral for cancer prevention measures. It may be useful to aim future interventions at healthcare professionals rather than patients to improve the prevention of familial cancer.

Patient experiences with gene panels based on exome sequencing in clinical diagnostics: high acceptance and low distress.

The Radboud University Medical Center was among the first to implement two-step exome sequencing in clinical genetic diagnostics. This study is the first to evaluate patient experiences with gene panels based on exome sequencing, using quantified psychological variables: acceptance, psychological distress, expectations of heredity and unsolicited findings. Between August 2011 and July 2012, 177 patients diagnosed with early-onset colorectal/kidney cancer, deafness, blindness or movement disorder consented to diagnostic exome sequencing offered by clinical geneticists. Baseline questionnaires were sent to 141 adults, returned by 111 with median age of 49 [22-79] years and positive family history in 81%. Follow-up included 91 responders at median 4 [2-22] weeks after results from known gene panels per diagnosis group; exome-wide analysis is ongoing. Confirmed or possibly pathogenic mutations were found in 31% with one unsolicited finding (oncogenetic panel). Most patients (92%) were satisfied. There were no significant changes in heredity-specific distress (18% at baseline, 17% at follow-up) and expectations of heredity. Fewer patients expected unsolicited findings at follow-up (29% vs 18%, p = 0.01). Satisfaction and distress were equal in those with vs without mutations. In conclusion, most adults accepted and were satisfied with gene panels based on diagnostic exome sequencing, few reporting distress.

Fourfold increased detection of Lynch syndrome by raising age limit for tumour genetic testing from 50 to 70 years is cost-effective.

BACKGROUND: Recognising colorectal cancer (CRC) patients with Lynch syndrome (LS) can increase life expectancy of these patients and their close relatives. To improve identification of this under-diagnosed disease, experts suggested raising the age limit for CRC tumour genetic testing from 50 to 70 years. The present study evaluates the efficacy and cost-effectiveness of this strategy. METHODS: Probabilistic efficacy and cost-effectiveness analyses were carried out comparing tumour genetic testing of CRC diagnosed at age 70 or below (experimental strategy) versus CRC diagnosed at age 50 or below (current practice). The proportions of LS patients identified and cost-effectiveness including cascade screening of relatives, were calculated by decision analytic models based on real-life data. RESULTS: Using the experimental strategy, four times more LS patients can be identified among CRC patients when compared with current practice. Both the costs to detect one LS patient (€9437/carrier versus €4837/carrier), and the number needed to test for detecting one LS patient (42 versus 19) doubled. When family cascade screening was included, the experimental strategy was found to be highly cost-effective according to Dutch standards, resulting in an overall ratio of €2703 per extra life-year gained in additionally tested patients. CONCLUSION: Testing all CRC tumours diagnosed at or below age 70 for LS is cost-effective. Implementation is important as relatives from the large number of LS patients that are missed by current practice, can benefit from life-saving surveillance.